Method for preparing levetiracetam and intermediates thereof

ABSTRACT

There is disclosed a method for preparing levetiracetam and intermediates from a compound of the formula: 
     
       
         
         
             
             
         
       
     
     wherein CR is selected from the group consisting of cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof.

FIELD OF THE INVENTION

This invention relates to N-(3-substituted propyl)-2-aminobutyronitrile, its preparation, and its use for preparing levetiracetam and intermediates thereof.

BACKGROUND OF THE INVENTION

Levetiracetam is the S-enantiomer of etiracetam in a class of medications called anticonvulsants. It is used in combination with other medications to treat certain type of seizures in adults and children with epilepsy. Levetiracetam has the following structure:

Although numerous methods have been developed for preparing levetiracetam, it is commercially produced by one of the two methods first disclosed in GB 1309692 and U.S. Pat. No. 4,696,943. In the first method, 2-pyrrolidinone and alkyl 2-halobutyrate are used as the starting materials in a process according to the following reaction scheme:

wherein X is halogen, HM is metal hydride, and R¹ is an alkyl group.

In the second method, L-2-aminobutanamide hydrochloride and alkyl 4-halobutyrate or 4-halobutyryl halide are used as the starting materials in a process according to the following reaction scheme:

wherein X is a halogen, R¹ is an alkyl group, and the base is an organic or inorganic base such as triethylamine or sodium carbonate.

There are inherent disadvantages in these two methods for the production of levetiracetam. In the process according to the first method, the metal hydride, which is required to deprotonate 2-pyrrolidinone, is dangerous to handle on a large scale and presents serious safety issues for the manufacturing plant. In addition, the alkyl 2-halobutyrate ester is not only unavailable commercially but also extremely obnoxious, posing environmental and occupational problems.

In the process according to the second method, just like the alkyl 2-halobutyrate in the process of the first method, alkyl 4-halobutyrate and 4-halobutyryl halide are also extremely obnoxious, posing the same environmental and occupational problems. In addition, L-2-aminobutanamide hydrochloride is specifically produced for levetiracetam and as a result is costly. L-2-aminobutanamide hydrochloride is produced either from racemic 2-aminobutanamide through optical resolution or from L-2-aminobutyric acid, which is not one of the naturally occurring L-amino acids, but is specifically produced for the purpose. Although there have been intensive efforts to improve the process for producing L-2-aminobutanamide hydrochloride and L-2-aminobutyric acid, they are still costly. In addition, during the cyclization under strongly basic condition, the product of levetiracetam is partially racemized or hydrolyzed. To obtain a product of pharmaceutical grade, extensive purification is required.

It is the object of the present invention to overcome these inherent disadvantages in the processes for preparing levetiracetam and to disclose a process for preparing levetiracetam and intermediates thereof from readily available starting materials. The process according to the present invention is concise, constructs all necessary structural elements in a one-pot synthesis, and reaches levetiracetam from commercially and economically available starting materials in far fewer steps than prior art processes.

SUMMARY OF THE INVENTION

This invention discloses novel intermediates of the following structural formula (II):

wherein CR is cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof; wherein the alkali is lithium, sodium, potassium or a mixture thereof; wherein the alkaline earth metal is magnesium, calcium, barium, or a mixture thereof; and wherein the alkyl refers to C₁-C₁₂ of a straight, cyclic, or branched chain alkane radical containing from 1 to 12 carbon atoms, preferably the alkyl is C₁-C₄. These intermediates are useful for the preparation of levetiracetam.

The present invention also relates to processes for preparing the intermediates of formula (II), comprising the reaction of propionaldehyde, a source of cyanide, and a primary amine of formula H₂NCH₂CH₂CH₂CR, wherein CR is cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof; and wherein the source of cyanide is alkali cyanide, alkaline earth metal cyanide, zinc cyanide, or hydrogen cyanide. The alkali is lithium, sodium, potassium, or a mixture thereof. The alkaline earth metal is magnesium, calcium, barium, or a mixture thereof.

The present invention further relates to various methods for preparing levetiracetam and intermediates thereof from the novel intermediate of formula (II) by converting it to the key precursor of levetiracetam having the following structural formula:

wherein R is hydrogen or a C₁-C₁₂ alkyl group.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “alkyl” refers to a straight, branched chain, or cyclic alkane (hydrocarbon) radical containing from 1 to 12 carbon atoms. Exemplary “alkyl” groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, isobutyl, cyclobutyl, cyclopropylmethyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. The term “C₁-C₁₂ alkyl” refers to a straight, cyclic, or branched chain alkane radical containing from 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, isobutyl, cyclobutyl, cyclopropylmethyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, and octyl.

The compounds of the present invention may form salts which are also within the scope of this invention. Reference to compounds of the formula (II) through (X) herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.

The compounds of the present invention may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, alkanoic acids, alkylsulfonic acids, aromatic sulfonic acids, isethionic acid, and the like.

The compounds of the present invention may also form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as lithium, sodium, potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) and salts with amino acids such as arginine, lysine and the like.

All stereoisomers of the present compounds (for example, those which may exist due to asymmetric carbons on various substituents), include enantiomeric forms and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid or base followed by crystallization, or biocatalytic methods, for example, selective hydrolysis with a lipase.

DESCRIPTION OF THE INVENTION

The present invention relates to N-(3-substituted propyl)-2-aminobutyronitrile having formula (II)

its preparation, and its use in preparing levetiracetam, wherein CR is a substituent selected from the group consisting of cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof.

The compound of formula (II) can be prepared economically and efficiently in a process comprised of reacting propionaldehyde, a source of cyanide, and a primary amine of formula H₂NCH₂CH₂CH₂CR, in a reaction as described in the following scheme:

wherein CR is cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof, and wherein MCN represents the source of cyanide such as alkali cyanide, alkaline earth metal cyanide, zinc cyanide, or hydrogen cyanide.

A particularly useful primary amine is gamma-aminobutyric acid or its derivative. The neutral gamma-aminobutyric acid, which is available commercially and economically, may be preferably used. The addition salts of gamma-aminobutyric acid with a variety of acids may also be used. Alkyl esters of gamma-aminobutyric acid are also suitable for the reaction. In addition, basic salts of gamma-aminobutyric acid can be used in the reaction. Preferably, alkali or alkaline earth metal gamma-aminobutyrate is prepared in situ by hydrolysis of 2-pyrrolidinone with an alkali hydroxide, or an alkaline earth metal oxide, or an alkaline earth metal hydroxide, or their mixture. The basic agent for the hydrolysis of 2-pyrrolidinone is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium oxide, magnesium hydroxide, calcium oxide, calcium hydroxide, barium oxide, barium hydroxide, and a mixture of two or more thereof.

The reaction to prepare the compound of formula (II) is carried out in an aqueous solution and optionally in the presence of an organic solvent. A suitable solvent is water-soluble and is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, tetrahydrofuran, dioxane, methoxyethanol, ethoxyethanol, and a mixture thereof.

The method of preparing the compound of formula (II) according to the present invention also comprises reacting the Schiff base of the following formula:

with a source of cyanide, wherein the Schiff base may be prepared in situ, comprising reacting propionaldehyde with a primary amine of the formula H₂NCH₂CH₂CH₂CR, wherein CR is cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof.

The method of preparing the compound of formula (II) according to the present invention further comprises reacting the cyanohydrin of propionaldehyde of the following formula:

with a primary amine of the formula H₂NCH₂CH₂CH₂CR, wherein CR is cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof. The cyanohydrin of propionaldehyde can be prepared from the reaction of propionaldehyde and a source of cyanide such as such as alkali cyanide, alkaline earth metal cyanide, zinc cyanide, or hydrogen cyanide. The cyanohydrin can be prepared in situ and used as such or isolated as a pure product and then used.

After its preparation, the compound of formula (II) may be isolated from the reaction mixture. On the other hand, it may also be used as such to prepare levetiracetam according to various methods disclosed herein. The methods for preparing levetiracetam are illustrated in the following reaction schemes. Solvents, temperature, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art.

In the first embodiment of the present invention to prepare levetiracetam, the compound of formula (II) is converted to (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) in a process comprising the steps according to the following reaction scheme:

wherein M is an alkali or an alkaline earth metal or their mixture. The alkali is lithium, sodium, potassium, or a mixture. The alkaline earth metal is magnesium, calcium, barium, or a mixture.

In this aspect of the first embodiment of the present invention, the cyano group in the compound of formula (II) is first hydrolyzed to the carboxylate by using a base. A suitable base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, magnesium oxide, calcium oxide, barium oxide, and a mixture of two or more thereof. The resulting carboxylate salt is acidified to form 2-N-(3-carboxypropyl)-aminobutyric acid of formula (III) by adding an acid. A suitable acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, lower alkanoic acid, alkylsulfonic acid, aromatic sulfonic acid, and a mixture thereof.

The compound of formula (III) can be readily isolated from the solution by adjusting the pH to a range from 3 to 5, at which point, the compound precipitates from the solution. The compound of formula (III) is readily isolated by a method of solid-liquid separation techniques, such as filtration or centrifuge. On the other hand, the compound of formula (III) may be used in the solution for further reaction without being isolated.

It has now been found that the intermediate of formula (III) can be cyclized to form (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV), the key intermediate and a well-known precursor to levetiracetam, under various reaction conditions.

In one method to prepare the key intermediate of formula (IV), the intermediate of formula (III) is heated to melt while removing the water formed during the cyclization. After no more water is released, the cyclization is complete. The product can be recrystallized from water or used for the next step of the process.

In another method to prepare the key intermediate of formula (IV), the intermediate of formula (III) is suspended in a solvent of a boiling point of at least 100° C. and heated to reflux to perform the cyclization reaction while removing the water formed. A suitable solvent is selected from the group consisting of toluene, xylenes, trimethylbenzenes, cumene, cymene, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, C₄-C₁₀ alcohols, and C₂-C₈ alkanoic acids.

In a further method to prepare the key intermediate of formula (IV), the intermediate of formula (III) is suspended in water and is heated to a temperature from 90° C. to 260° C. under autogenous pressure or increased pressure to perform the cyclization reaction from (III) to (IV). Preferably, the reaction temperature is from 110° C. to 180° C., more preferably, from 120° C. to 160° C., and most preferably, from 130° C. to 150° C. After the reaction, the product precipitates from the aqueous solution upon cooling. After separation of the product of formula (IV) by a solid-liquid separation, the mother liquor can be used to suspend a new batch of the intermediate (III) and to perform the cyclization reaction. This cyclic process of the cyclization of the intermediate (III) results in a quantitative yield of the key intermediate (IV) without using any additional reagent.

It is particularly advantageous to carry out all steps of reactions leading to the key intermediate of formula (IV) in a one-pot synthesis, without the tedious isolation of any intermediate. This one-pot process of multiple reactions according to the present invention results in a concise process for preparing levetiracetam from basic starting materials such as 2-pyrrolidinone, a source of cyanide, and propionaldehyde.

In this embodiment of the instant invention, 2-pyrrolidinone is hydrolyzed to an alkali or an alkaline earth metal gamma-aminobutyrate by using a base. A suitable base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, magnesium oxide, calcium oxide, barium oxide, and a mixture of two or more thereof. To the solution of the alkali or alkaline earth metal gamma-aminobutyrate is added a source of cyanide, i.e., alkali cyanide, followed by the addition of propionaldehyde. Preferably, after 2-pyrrolidinone is hydrolyzed to an alkali or alkaline earth metal gamma-aminobutyrate, the strongly basic solution is neutralized with an acid before the addition of alkali cyanide and propionaldehyde. After the formation of the intermediate of formula (II) is complete, to the solution is then added a base to hydrolyze the cyano group. A suitable base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, magnesium oxide, calcium oxide, barium oxide, and a mixture of two or more thereof. The strongly basic solution is then acidified with an acid and heated to yield the key intermediate of formula (IV). A suitable acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, lower alkanoic acid, alkylsulfonic acid, aromatic sulfonic acid, and a mixture thereof.

For the hydrolysis of 2-pyrrolidinone and the cyano group in the compound of formula (II), different base may be used, but it is preferable to use the same base. Preferably, an alkali hydroxide is used. Most preferably, sodium hydroxide is used. For the acidification of solutions comprised of alkali or alkaline earth metal salts of gamma aminobutyrate and the compound of formula (III), different acid may be used. Preferably, the same acid is used. Most preferably, sulfuric acid is used.

The temperature for the compound of formula (III) to form the compound of formula (IV) is from 90° C. to 260° C., preferably from the refluxing temperature of the solution comprised of the compound of formula (III) to 160° C., more preferably from 120° C. to 150° C., most preferably from 130° to 140° C. The pressure for the reaction is from autogenous to an increased pressure. The reaction may be carried out discontinuously, semi-continuously, or continuously. The overall molar yield of the key intermediate of formula (IV) in this one-pot process is at least 50%, particularly more than 70%, more particularly more than 80%, most particularly more than 85%.

The racemic compound of formula (IV) is then optically resolved by using an optically active resolving agent. A suitable resolving agent can be selected from those listed in David Kozma, CRC Handbook of Optical Resolution via Diastereomeric Salt Formation, 2002, CRC Press, which is incorporated herein in its entirety. After optical resolution of the S-enantiomer, the R-enantiomer is racemized to the racemic form and subjected to optical resolution again. This cyclic resolution and racemization yield the S-enantiomer of formula (V) in a yield of more than 50%, particularly more than 75% to nearly quantitative 100%.

The optically pure S-enantiomer of formula (V) can be readily converted to levetiracetam of formula (I) by one of the amidation methods known in the prior art.

In the other aspect of the first embodiment of the present invention, the key intermediate of formula (IV) is prepared directly by reacting the compound of formula (II) with an acid to hydrolyze the nitrile group and to form the key intermediate of formula (IV) in situ in a process comprising the steps according to Reaction Scheme 2:

wherein CR is cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof.

A suitable acid is selected from the group consisting of sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, alkylsulfonic acid, aromatic sulfonic acid, and a mixture of two or more thereof. Preferably, sulfuric acid is used to transform the compound of formula (II) to the intermediate of formula (IV).

In this embodiment of the instant invention, 2-pyrrolidinone is hydrolyzed with a base to an alkali or alkaline earth metal gamma-aminobutyrate. A suitable base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, magnesium oxide, calcium oxide, barium oxide, and a mixture of two or more thereof. Preferably, after the hydrolysis of 2-pyrrolidinone, the strongly basic solution is neutralized with an acid before the addition of alkali or alkaline earth metal cyanide and propionaldehyde. To the solution comprised of alkali or alkaline earth metal gamma-aminobutyrate is added a source of cyanide, i.e., alkali cyanide, followed by the addition of propionaldehyde. After the formation of the intermediate of formula (II) is complete, to the solution is then added an acid to hydrolyze the nitrile group and to cyclize the aminobutyric acid group to yield the key intermediate of formula (IV). A suitable acid is selected from the group consisting of sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, alkylsulfonic acid, aromatic sulfonic acid, and a mixture of two or more thereof. The temperature for the compound of formula (III) to form the compound of formula (IV) is from 90° C. to 260° C., preferably from the refluxing temperature of the solution comprised of the compound of formula (III) to 160° C., more preferably from 120° C. to 150° C., most preferably from 130° to 140° C. The pressure for the reaction is from autogenous to an increased pressure. The reaction may be carried out discontinuously, semi-continuously, or continuously. The overall yield of the key intermediate of formula (IV) in this one-pot process is at least 50%, particularly more than 70%, more particularly more than 80%, most particularly more than 85%.

The one-pot process to prepare the intermediate of formula (IV) according to the present invention results in a concise process for preparing levetiracetam from basic starting materials such as 2-pyrrolidinone, a source of cyanide, and propionaldehyde.

In the second embodiment of the present invention to prepare levetiracetam, the compound of formula (II) is converted to the key intermediate of formula (IV) according to methods described in the first embodiment of the present invention and then to an ester of formula (VI) by reacting the compound of formula (IV) with an alcohol of the formula R¹OH, wherein R¹ is a C₁-C₁₂ alkyl group, preferably, C₁-C₄ alkyl group. This racemic ester of formula (VI) is optically resolved by using a lipase to selectively hydrolyze the ester to an optically active ester (VII) and an optically active acid, which is used to prepare levetiracetam in a process comprising the steps according to the following reaction scheme:

wherein CR is cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof; and R¹ is a C₁-C₁₂ alkyl group, preferably, a C₁-C₄ alkyl group.

The S-enantiomer of the ester is subject to an amidation reaction to form levetiracetam of formula (I) by methods known in the prior art, while the R-enantiomer of the acid is subject to a racemization reaction to form (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV), which can be reacted with an alcohol R¹OH to form the starting ester of the formula (VI) for the resolution with the lipase.

In the third embodiment of the present invention, the compound of formula (II) is first converted to a diester of formula (VIII), which is then cyclized to the ester of formula (VI). The ester is then selectively hydrolyzed by a lipase to an optically active ester and an acid. Levetiracetam is prepared from the S-enantiomer of the ester.

wherein CR is cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof; and R¹ is a C₁-C₁₂ alkyl group, preferably, a C₁-C₄ alkyl group.

The formation of the diester of formula (VIII) is performed by reacting the compound of formula (II) with an alcohol R¹OH in the presence of an acid, wherein R¹ is a C₁-C₁₂ alkyl group, preferably, a C₁-C₄ alkyl group. A suitable acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, alkylsulfonic acid, and arylsulfonic acid. Preferably, sulfuric acid is used. The formed diester may be isolated or used directly for the cyclization to form the compound of formula (VI). The cyclization reaction is carried out with a base and optionally in the presence of a phase transfer catalyst. A suitable base is selected from the group consisting of organic bases, alkali hydroxide, alkali carbonate, alkali phosphate, alkali sulfite, alkaline earth metal hydroxide, alkaline earth metal oxide, or a mixture thereof. A suitable phase transfer catalyst is selected from the group consisting of quaternary ammonium salts and quaternary phosphonium salts. Preferably, benzyltriethylammonium chloride or tetrabutylammonium bromide is used. Organic bases are also useful particularly useful for the cyclization. Suitable organic bases are pyridines and ternary amines. A suitable organic base is selected from the group consisting of trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, pyridine, picolines, 2-methy-5-ethylpyridine, dimethylpyridines, trimethylpyridines, DABCO, and a mixture thereof.

The S-enantiomer of the ester of the formula (VII) is subject to an amidation reaction to form levetiracetam of formula (I) by methods known in the prior art, while the R-enantiomer of the acid is subject to a racemization reaction to form (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV), which can be reacted with an alcohol R¹OH to form the starting ester of the formula (VI) for the resolution with the lipase.

In the fourth embodiment of the present invention, the compound of formula (II), wherein CR is an alkyl carboxylate, i.e., COOR¹, is cyclized to an intermediate of formula (IX):

wherein R¹ is a C₁-C₁₂ alkyl group. Preferably, R¹ is a C₁-C₄ alkyl group.

The formation of the compound of formula (IX) is carried out with a base and optionally in the presence of a phase transfer catalyst. A suitable base is selected from the group consisting of organic bases, alkali hydroxide, alkali carbonate, alkali phosphate, alkali sulfite, alkaline earth metal hydroxide, alkaline earth metal oxide, or a mixture thereof. A suitable phase transfer catalyst is selected from the group consisting of quaternary ammonium salts and quaternary phosphonium salts. Preferably, benzyltriethylammonium chloride or tetrabutylammonium bromide is used. Organic bases are also useful particularly useful for the cyclization. Suitable organic bases are pyridines and ternary amines. A suitable organic base is selected from the group consisting of trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, pyridine, picolines, 2-methy-5-ethylpyridine, dimethylpyridines, trimethylpyridines, DABCO, and a mixture thereof.

The nitrile group in the compound of (IX) can be hydrolyzed with an acid to a carboxylic acid to obtain the intermediate of formula (IV) or reacted with an alcohol R¹OH in the presence of an acid to form an ester to form the compound of formula (VI), wherein R¹ is a C₁-C₁₂ alkyl group, preferably, R¹ is a C₁-C₄ alkyl group. A suitable acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, alkylsulfonic acid, arylsulfonic acid, and a mixture thereof. These two intermediates are then optically resolved and converted to levetiracetam according to methods described in the first and second embodiments of the present invention.

EXAMPLES

The following examples will illustrate the practice of this invention but are not intended to limit its scope.

Example 1

To a solution comprised of 300 mL of water, 50 g of sodium cyanide, and 105 g of gamma butyric acid in a 1 L flask was dropwise added 58.0 g of propionaldehyde while maintaining the temperature below 25° C. After being stirred for 2 hours at room temperature, the solution was found to be comprised of 2-N-(sodium carboxylpropyl)-aminobutyronitrile of formula (II) in a molar yield of about 95%. LC-MS+1: 171. The solution was used without further purification.

Example 2

To a solution comprised of 300 mL of water, 50 g of sodium cyanide, and 105 g of gamma butyric acid in a 1 L flask was dropwise added 58.0 g of propionaldehyde while maintaining the temperature below 25° C. After the solution was stirred for 2 hours at room temperature, 60 g of sodium hydroxide was added and the solution was heated to reflux for 2 hours. Then, sulfuric acid was added to a pH of 3-4. After cooling to room temperature, the precipitated solid material was filtered and washed with ice water to yield 125 g of 2-N-(carboxylpropyl)aminobutyric acid of formula (III). MS+1: 190.

Example 3

40.0 g of 2-N-(carboxylpropyl) aminobutyric acid was suspended in 200 mL of water containing 5 g of sulfuric acid in a glass pressure bottle. The suspension was heated to obtain a clear solution to 150° C. and maintained at the same temperature for 4 hours. After cooling to room temperature, crystalline solid was formed and filtered to yield 31 g of (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) as a white material. M.P. 154-156. MS+1: 172.

Example 4

To a solution comprised of 300 mL of water, 50 g of sodium cyanide, and 105 g of gamma butyric acid in a 1 L flask was dropwise added 58.0 g of propionaldehyde while maintaining the temperature below 25° C. The solution was stirred for 2 hours at room temperature before 150 g of sulfuric acid was added to the solution. The solution was placed in a pressure glass bottle and stirred in the bath at a temperature of 140-145° C. for 1 hours. Upon stopping the stirring, an oil phase was observed to separate. Further cooling to room temperature resulted in the formation of beige crystalline solid. Recrystallization from water with a small amount of decoloring charcoal yielded (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) as a white crystalline solid M.P. 154-156. MS+1: 172.

Example 5

To a solution comprised of 300 mL of water, 50 g of sodium cyanide, and 105 g of gamma butyric acid in a 1 L flask was dropwise added 58.0 g of propionaldehyde while maintaining the temperature below 25° C. After the solution was stirred for 2 hours at room temperature, 60 g of sodium hydroxide was added and the solution was heated to reflux for 2 hours. Then, sulfuric acid was added to a pH of 2.0. 140 g of sulfuric acid was used. The solution was then heated to 150° C. for 4 hours in an autoclave under autogenous pressure. After cooling to room temperature, the precipitated solid material was filtrated and washed with water. The off-white material was dissolved in hot water and decolorized with a little activated carbon to yield (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) as a white crystalline solid. M.P. 154-156° C. MS+1: 172.

Example 6

To a solution comprised of 60 g of sodium hydroxide and 250 mL of water was added 90 g of 2-pyrrolidinone. After the solution was refluxed for 2 hours, 50 g of sodium cyanide was added, followed by a dropwise addition of 58 g of propionaldehyde, while maintaining the temperature below 25° C. To the solution was then added 40 g of sodium hydroxide and the solution was refluxed for 2 hours. Then, sulfuric acid was added to a pH of 2.0. 160 g of sulfuric acid was used. The solution was then heated to 150° C. for 4 hours in an autoclave under autogenous pressure. After cooling to room temperature, the precipitated solid material was filtrated and washed with water. The off-white material was dissolved in hot water and decolorized with a little activated carbon to yield (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) as a white crystalline solid. M.P. 154-156° C. MS+1: 172.

Example 7

To 500 mL of toluene was added 170 g of white recrystallized (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) and 121 g of R-(+)-α-phenylethylamine. The solution was briefly heated to 90° C. Upon cooling to room temperature, crystalline salt formed, which was filtered. This salt was purified by heating to dissolve in 350 mL of toluene. The solution was cooled and filtered to obtain the R-(+)-α-phenylethylamine salt of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (V).

The salt was dissociated in 300 mL of deionized water containing 12 g of sodium hydroxide. After the R-(+)-α-phenylethylamine was removed by extraction with toluene two times, the aqueous solution was acidified to pH 2-3 with sulfuric acid. The mixture was cooled on ice and the crystals were filtered off to obtain (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (V). M.P. 124-126° C.

40 g of the (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (V) was dissolved in 200 mL of anhydrous methanol containing 0.1 g of p-toluenesulfonic acid. After the solution was refluxing 2 hours to form the methyl ester, the solution was cooled on ice and ammonia was passed to the solution. The solution was kept at room temperature for 16 hours. After the excess ammonia and methanol were removed under vacuum, the residual solid was recrystallized in ethyl acetate to obtain 32 g of (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide of formula (I). M.P. 117-118° C.

It will be understood that the foregoing examples, explanation, and drawings are for illustrative purposes only and that in view of the instant disclosure various modifications of the present invention will be self-evident to those skilled in the art. Such modifications are to be included within the spirit and purview of this application and the scope of the appended claims. 

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 13. (canceled)
 14. (canceled)
 15. (canceled)
 16. A Process for preparing (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV):

comprising: (a) hydrolyzing a compound of formula (II):

with an alkali hydroxide or an alkaline earth metal hydroxide to yield a product of the following formula:

wherein CR is selected from the group consisting of cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof; wherein the alkyl is C₁-C₁₂; wherein M is an alkali or an alkaline earth metal; wherein the alkali is lithium, sodium, potassium, or a mixture thereof; and wherein the alkaline earth metal is magnesium, calcium, barium, or a mixture thereof; (b) reacting the product of step (a) with an acid; and (c) cyclizing the product of step (b) to form (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV).
 17. The process according to claim 16, wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, lower alkanoic acid, alkylsulfonic acid, aromatic sulfonic acid, and a mixture thereof.
 18. The process according to claim 16, wherein the cyclizing reaction of the compound of formula (II) to form (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) is carried out by heating.
 19. The process according to claim 16, further comprising producing levetiracetam of formula (I) from the compound of formula (IV)) by a process which comprises the steps of: (1) resolving the (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) into optically active (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (V):

and (2) subjecting the (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (V) to an amidation reaction to form (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide of formula (I):


20. The process according to claim 16, further comprising producing levetiracetam of formula (I) from the compound of formula (IV)) by a process which comprises the steps of: (1) reacting the compound of formula (IV) with an alcohol R¹OH to form alkyl (RS)-α-ethyl-2-oxo-1-pyrrolidineacetate of formula (VI):

wherein R¹ is C₁-C₁₂; (2) resolving the alkyl (RS)-α-ethyl-2-oxo-1-pyrrolidineacetate of formula (VI) into (R)-α-ethyl-2-oxo-1-pyrrolidineacetic acid and alkyl (S)-α-ethyl-2-oxo-1-pyrrolidineacetate of formula (VII):

with a lipase; and (3) subjecting the alkyl (S)-α-ethyl-2-oxo-1-pyrrolidineacetate of formula (VII) to an amidation reaction to form (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide of formula (I):


21. The process according to claim 16, wherein the compound of formula (II)

is prepared by mixing propionaldehyde, a source of cyanide, and a primary amine of formula H₂NCH₂CH₂CH₂CR in an aqueous solution or an aqueous solvent; wherein CR is selected from the group consisting of cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof; wherein the alkyl is C₁-C₁₂; wherein the source of cyanide is selected from the group consisting of alkali cyanide, alkaline earth metal cyanide, zinc cyanide, and hydrogen cyanide; wherein the alkali is lithium, sodium, potassium, or a mixture thereof; and wherein the alkaline earth metal is magnesium, calcium, barium, or a mixture thereof; and wherein the solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, tetrahydrofuran, dioxane, methoxyethanol, ethoxyethanol, and a mixture thereof.
 22. The process according to claim 16, wherein the compound of formula (II)

is prepared by reacting a compound of the following formula:

with a source of cyanide; wherein CR is selected from the group consisting of cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof; wherein the alkyl is C₁-C₁₂; wherein the source of cyanide is selected from the group consisting of alkali cyanide, alkaline earth metal cyanide, zinc cyanide, and hydrogen cyanide; wherein the alkali is lithium, sodium, potassium, or a mixture thereof; and wherein the alkaline earth metal is magnesium, calcium, barium, or a mixture thereof.
 23. The process according to claim 16, wherein the compound of formula (II)

is prepared by reacting a compound of the following formula:

with a primary amine of the formula H₂NCH₂CH₂CH₂CR, wherein CR is cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof; wherein the alkali is lithium, sodium, potassium, or a mixture thereof; wherein the alkaline earth metal is magnesium, calcium, barium, or a mixture thereof; and wherein the alkyl is C₁-C₁₂.
 24. The process according to claim 19, wherein the (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) is resolved into optically active (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (V) with a resolving agent selected from the group consisting of dehydroabietylamine, (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine, and D-(−)-threo-2-amino-1-(p-nitrophenyl)-1,3-propanediol.
 25. A process for preparing (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV):

comprising reacting a compound of formula (II):

with an acid; wherein CR is selected from the group consisting of cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof; and wherein the alkyl is C₁-C₁₂.
 26. The process according to claim 25, wherein the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, alkylsulfonic acid, aromatic sulfonic acid, and a mixture of two or more thereof.
 27. The process according to claim 25, further comprising producing levetiracetam of formula (I) from the compound of formula (IV)) by a process which comprises the steps of: (1) resolving (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) into optically active (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (V):

and (2) subjecting the (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (V) to an amidation reaction to form (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide of formula (I):


28. The process according to claim 25, further comprising producing levetiracetam of formula (I) from the compound of formula (IV)) by a process which comprises the steps of: (1) reacting the compound of formula (IV) with an alcohol R¹OH to form alkyl (RS)-α-ethyl-2-oxo-1-pyrrolidineacetate of formula (VI):

wherein R¹ is C₁-C₁₂. (2) resolving the alkyl (RS)-α-ethyl-2-oxo-1-pyrrolidineacetate of formula (VI) into (R)-α-ethyl-2-oxo-1-pyrrolidineacetic acid and alkyl (S)-α-ethyl-2-oxo-1-pyrrolidineacetate of formula (VII):

with a lipase; and (3) subjecting the alkyl (S)-α-ethyl-2-oxo-1-pyrrolidineacetate of formula (VII) to an amidation reaction to form (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide of formula (I):


29. The process according to claim 25, wherein the compound of formula (II):

is prepared by mixing propionaldehyde, a source of cyanide, and a primary amine of formula H₂NCH₂CH₂CH₂CR in an aqueous solution or an aqueous solvent; wherein CR is selected from the group consisting of cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof; and wherein the alkyl is C₁-C₁₂; wherein the source of cyanide is selected from the group consisting of alkali cyanide, alkaline earth metal cyanide, zinc cyanide, and hydrogen cyanide; wherein the alkali is lithium, sodium, potassium, or a mixture thereof; and wherein the alkaline earth metal is magnesium, calcium, barium, or a mixture thereof; and wherein the solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, tetrahydrofuran, dioxane, methoxyethanol, ethoxyethanol, and a mixture thereof.
 30. The process according to claim 25, wherein the compound of formula (II)

is prepared by reacting a compound of the following formula:

with a source of cyanide; wherein CR is selected from the group consisting of cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof; wherein the alkyl is C₁-C₁₂; wherein the source of cyanide is selected from the group consisting of alkali cyanide, alkaline earth metal cyanide, zinc cyanide, and hydrogen cyanide; wherein the alkali is lithium, sodium, potassium, or a mixture thereof; and wherein the alkaline earth metal is magnesium, calcium, barium, or a mixture thereof.
 31. The process according to claim 25, wherein the compound of formula (II)

is prepared by reacting a compound of the following formula:

with a primary amine of the formula H₂NCH₂CH₂CH₂CR, wherein CR is cyano, carboxylic acid, carboxamide, alkali carboxylate, alkaline earth metal carboxylate, alkyl carboxylate, and a mixture thereof; wherein the alkali is lithium, sodium, potassium, or a mixture thereof; wherein the alkaline earth metal is magnesium, calcium, barium, or a mixture thereof; and wherein the alkyl is C₁-C₁₂.
 32. The process according to claim 27, wherein the (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) is resolved into optically active (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (V) the with a resolving agent selected from the group consisting of dehydroabietylamine, (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenyl ethyl amine, and D-(−)-threo-2-amino-1-(p-nitrophenyl)-1,3-propanediol. 